Project Summary Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly human malignancies, with dismal long- term survival and limited advances in treatment. PDAC cancer cells are located in a complex tumor microenvironment (TME) comprising multiple cell types and an extensive desmoplastic reaction that can constitute up to 90% of the tumor volume. The contributions of the TME to the maintenance of PDAC cancer cells are not well understood at the molecular level, and therefore, the development of preventive and therapeutic strategies has been challenging. Pancreatic stellate cells (PSC) are key mediators of inflammation and the fibrotic stroma in the TME. Understanding PSC interactions with other TME cell types may identify therapeutic targets for PDAC. Our long-term goal is to understand molecular cross talk between cells in the PDAC TME, so that key factors in this process may be disrupted for future preventive and therapeutic strategies. Lipocalin- 2 (LCN2) is a secreted protein expressed by immune (neutrophils and macrophages) and tumor cells. LCN2 plays an important role in inflammation and immune modulation. Studies have looked at the role of LCN2 in some cancers, but focused only on its tumor cell-intrinsic role or its systemic levels. For example, LCN2 expression levels are highly elevated in the plasma and tumor cells of many cancers, including PDAC, and correlate with malignant progression. However, there is a gap in knowledge about the direct mechanistic function of LCN2 in the TME and its potential to serve as a target for cancer therapy. Our preliminary data provide evidence of LCN2 promoting tumor progression and reveal a previously unknown role of LCN2 in the PDAC TME. These observations suggest a mechanistic link between LCN2, inflammation, and PDAC by signaling PSC. The overall goals of this project are to determine how LCN2 contributes to the development and progression of PDAC and assess its efficacy as a therapeutic target. Hypothesis: LCN2, as a major regulator of inflammation, drives tumor progression and development by promoting the PSC to secrete pro-inflammatory cytokines in the PDAC TME, and serves as a novel therapeutic target. Aim 1: Determine how cell type-specific LCN2 secretion contributes to PDAC development. Aim 2: Identify the role of LCN2 signaling in PSC and its contribution to PDAC development. Aim 3: Assess the therapeutic efficacy of LCN2 blockade in PDAC. Impact: Our data will provide a detailed understanding of sources of LCN2 and the importance of cell type-specific LCN2- mediated signaling pathways that regulate TME PDAC inflammation. The results will provide important insights to guide the development of new preventive and therapeutic therapies for this lethal disease, through blockade of LCN2 and/or LCN2-associated signaling pathways.